This invention relates to controlling the temporal response of mass spectrometers, and particularly to detecting ions of interest by mass spectrometry, wherein ions are processed through a section of a mass spectrometer that operates under conditions enabling ion-neutral collisions. More particularly, this invention is concerned with a technique to enable an existing charge distribution in such a processing section to be flushed out rapidly and then quickly reestablished, so as to give, at an output, a reproducible and quickly repeatable ion current, thereby to give better control of the temporal response.
In mass spectrometry, a reaction and/or collision cell is often employed (to remove an isobaric interference through reaction or fragmentation with a reaction/collision gas, or shift the ion of interest to another mass by reacting with a reaction gas, or fragment the ion of interest and collect the fragment ions for subsequent mass analysis). Collision or reaction cells have the problem that, due to the high pressure necessary present within them, flow of ions can be slowed. In a variety of standard mass spectrometer operating regimes, this can cause difficulties, since it is often required to switch, rapidly, between different top operating states. However, for collision cells, when the operating state is changed, it can take some time for an output ion stream to stabilize, due to the slow ion motion through the collision cells and space charge effects within the collision cell. There are also other sections of standard mass spectrometer systems which can also slow motion of ions and show slow response times to changes in operating conditions. For example, some mass spectrometers can have mass analysis sections that operate at relatively high pressures, and, in many mass spectrometer systems, it is common to have an input section with a focusing multipole device interposed between an atmospheric pressure source and the high vacuum sections of the mass spectrometer, the input section operating at some intermediate pressure. Thus, all these sections pose problems for an operating scheme where the operating state is required to change rapidly.
It is also to be recognized that, in the field of mass spectrometry, there are large numbers of different mass spectrometers. For many purposes, these can be broken down into two broad categories. In one category, mass spectrometers are configured to analyze inorganic analytes. One common technique is inductively coupled plasma mass spectrometry (ICP-MS). An inductively coupled plasma source has, for example, an argon gas that is excited by inductive heating, to generate a plasma. The analyte is then injected into the plasma, where it is ionized. While this does effectively ionize the analyte, the resultant ion stream into the mass spectrometer provides a very large ion current, including a significant proportion of argon ions or other ions derived from the sample. This can lead to significant space charge effects within a collision/reaction cell.
The second significant category of mass spectrometers is that intended for analyzing organic compounds or analytes. Organic compounds commonly have large, complex structures, and must be ionized with some care, to avoid unwanted degradation or premature fragmentation of the analytes. Common ionization techniques include electrospray, nanospray and the like. Other ionization sources include glow discharge, microwave induced plasma, (both of these are also quite common in inorganic mass spectrometry) corona discharge, etc. It is becoming common practice, for analysis of organic compounds, to provide complex reaction schemes, where analytes are fragmented by collision or reaction, and a particular fragment is selected and then subject to a subsequent stage of collision or reaction. Systems have been proposed that would enable any desired number of steps of fragmentation and ion selection to be affected. It will also be understood that, within any mass spectrometer system, a variety of different reaction/collision cells (e.g. high order multipoles, ring guides and the like) can be used, and similarly that a variety of mass analysis sections can be employed (e.g. time of flight, magnetic sectors, ions traps, etc.).
Some of the inventors of the present application had previously developed an improvement to the basic ICP-MS system that provides for applying a pass band, to the collision cell. This mass spectrometer system is now identified as a Dynamic Reaction Cell (DRC) and is marketed by the assignee of the present invention. This essentially recognizes that while true mass filtering cannot be achieved in the collision cell, it is possible to apply a pass band, so as to reject ions that have m/z ratios substantially different from an ion of interest. This can be used to interrupt sequential chemistry that occurs within the collision cell, which can result in interferences with ions of interest. This Dynamic Reaction Cell is disclosed in U.S. Pat. No. 6,140,638, and like other instruments with collision/reaction cells, there can be problems in the time taken for the reaction cell to reach equilibrium following a change in operating conditions.
As noted, a problem with a collision cell is that when there is any substantial change in the operating condition, e.g. a change in the input ion current or change in fields applied to the cell, this should be reflected in the ion current output from the collision cell, but often it takes some time for the establishment of a new, stable charge distribution within the cell. During this time, an ion stream extracted from the cell can show fluctuations or transients. As ion motion is slowed within the collision/reaction cell, it simply takes time for ions to travel through the collision/reaction cell. Particularly for ICP-MS, the stronger ion current leads to a strong space charge effect, which can also significantly affect the ion density distribution and slow down changing of the ion population to reflect the new operating state. The present inventors have observed prolonged recovery of tho ion population, when the ion density is changed through a wide variety of different inputs. If the degree to which the ion density is changed is variable, the period of recovery is also variable.
It is to be noted that in the case of the DRC, common practice is for the bandpass of the, or the electrical parameters of the, reaction cell to be adjusted in concert with the mass selected by a down stream mass analyzer. Capacitive coupling between the collision/reaction cell and the mass analyzer can be provided but generally this does not provide the required bandpass. When a large jump in mass is executed, with the band pass of the DRC concomitantly adjusted, this can result in dominant ions previously included in the band pass being excluded, or vice versa. Typically, following a large jump in mass, the ion signal from the collision/reaction cell is initially suppressed and increases to a stable level but it is possible that the opposite could occur.
The issue of moving ions through pressurized sections of mass spectrometers, more specifically through collision cells, has been addressed in instruments intended primarily for analyzing organic analytes. Thus, U.S. Pat. No. 5,847,386 (assigned to the assignee of the present invention) discloses a mass spectrometer which provides for an axial field in high pressure sections of a mass spectrometer. These high pressure sections, in the disclosed embodiment, have quadrupole rod sets and a number of techniques are disclosed for applying the axial field to these rod sets. For example, the rods can be specifically shaped or orientated to generate the axial field, or an auxiliary rod set can be provided to generate the axial field, or the rod set can be segmented, to enable segments to be held at different DC potentials.
U.S. Pat. No. 5,847,386 is primarily concerned with a triple quadrupole instrument, in which a collision cell is located between two mass analysis sections. It proposes using the axial field to promote motion of ions through the collision cell, and in particular to promote clearing out of ions from the collision cell, when the operating state is changed. This also has the additional advantage of improving sensitivity, often by a factor of 2 to 5 in practice. As is known, such triple quadrupole instruments are often scanned over a range of masses, with each measurement being taken in a relatively short time period, so that it is essential that there is no leaking out of ions from a previous operating state, after the mass spectrometer has been switched to a second operating state to detect a different ion. The patent notes that it is common practice to provide a first quadrupole rod set, commonly identified as Q0 for focusing and directing ions and providing an interface between an atmospheric pressure source and a low pressure mass analyzer section. It additionally notes that, for reasons of economy, it is common for Q0 to be provided with an RF supply from the downstream mass analyzer through capacitors. When there is a jump or significant change in RF and/or DC voltages applied to the mass analyzer, transient processes delay establishment of the desired voltages on the Q0, resulting in ejection of some ions from Q0. It is stated that mass spectrometer builders have lived with this problem because of the very high cost of providing a separate RF power supply for Q0. It is then suggested that by providing an axial field in Q0, the time to refill Q0 can be reduced. Thus, the teaching is that clearing all the ions out of a section of the mass spectrometer is generally undesirable, and there is no recognition that being able to establish a repeatable, emptied state for a section of the instrument may have advantages. Further, due to the intended application of this type of mass spectrometer, there is no discussion of the space charge effects, and particularly no recognition that a substantial space charge barrier can clay a significant role in preventing rapid response of a collision/reaction cell to changing operating conditions.
While providing a linear axial field has many advantages, it does not, by itself, necessarily result in a rapid response of a collision cell. It can reduce the transit time of ions through the cell. However, if the space charge is significant relative to the applied field, the effectiveness of the axial field in establishing the necessary gradient to drag or accelerate ions through the cell is reduced, i.e. if a space charge barrier exists within the cell, an applied axial field can be off-set or shielded by the space charge. However, where the initial space charge is small relative to the applied field, the application of the field establishes an axial gradient that sets up a condition that minimizes formation of a space charge barrier within the cell. Provided the space charge of ions within the cell is insignificant relative to the applied field, a fast temporal response is obtained and a measured ion signal is reproducible, so that the settling time may be reduced. Alternatively, provided the charge distribution within the cell is approximately unchanged (or at least that the space charge field remains relatively constant relative to the applied fields), a fast temporal response is obtained and the measured ion signal is reproducible, though the signals may be suppressed, so that again settling time may be reduced.
Before the introduction of the commercial version of the DRC, it had been recognized by some of the present inventors that the slow recovery of the ion signal following a change of the DRC bandpass causes suppressed signals if insufficient time (called the settling time) is allowed for recovery. It was also recognized that the reproducibility of the state of the DRC after such a change was dependent on the current and mass distribution of the ions introduced into the cell. To partially address this problem, an optional flush pulse was implemented in the DRC product to reproducibly define the state of the DRC after each bandpass change (before each measurement) though it was not obvious to the user that this option was available. The slow recovery following the flush pulse could not be addressed at that time. As a result, although reproducible signals could be achieved in most cases by applying the flush pulse, those signals were typically unacceptably lower than a steady state signal when a practical (relatively short) settling time was allowed. As a result, the flush pulse although available for use was rarely if ever used in practice. It is also the inventors"" understanding that similar functionality is available on other products and from other manufacturers though it is unclear whether or not this generally known.
It should be realized that the flush pulse method alone does not necessarily provide for reproducible signals in the instance that the composition of the sample is changed, since the ion distribution that reestablishes during the settling period can be affected by the presence of absence of, for example, a concomitant element. That is, the settling time that is sufficient for signal recovery to a particular reproducible level after a certain bandpass change for one sample may allow the signal for the same analyte ion at the same concentration in a different sample to recover to a completely different level, due to a difference in the concomitant elements and their concentration between the samples. Also, since the measurement is usually performed on a recovering, i.e., changing, signal, the result of the measurement is dependent on the measurement duration (often called the dwell time), so that the number of ions detected per unit time depends on the dwell time.
It is to be appreciated that the flush pulse technique and the axial field technique are essentially opposite techniques, though they may be attempting to deal with the same problem, i.e. the slow response of collision cells and reaction cells and high pressure regions, e.g. mass analysis sections that operate under pressures sufficient to affect ion transport of mass spectrometers to changing operating states. The flush pulse fundamentally is Intended, in each instance, to flush out the existing charge distribution, so as to return the collision, reaction cell or other section of the mass spectrometer to a known, emptied state. This certainly can give a reproducible response, but as it can take some time for the charge to reestablish itself, this can make the temporal response longer. On the other hand, the use of an axial field takes an opposite approach. It does not attempt to flush out any preexisting charge distribution, but rather applies the field to accelerate ions, with the intention of reducing residence times within a collision cell or the like thereby causing an ion population to change more quickly when the operating state is charged.
What the present inventors have realized is that combining a flush pulse with an axial field can, surprisingly, provide a number of advantages. A flush pulse provides a reproducible charge distribution at the start of the settling period, again because the collision/reaction cell of the mass spectrometer system will always be starting from the same, emptied state. Consequently, the resultant signal should be less dependent, it not wholly independent, on the prior charge distribution within the cell. At the same time, the axial field provides rapid transit of ions during the settling period, resulting in rapid refilling of a collision cell or the like. This in turn results in a rapid response time, so that the settling time may be reduced. Because the flush pulse eliminates the dependence of the ion signal on the prior charge distribution history of the cell, and because the axial field provides rapid response, the combination provides a rapid temporal response. Although the time required for full recovery of the signal to its steady state value may still depend on the composition of the sample, this time is made short by application of the axial field. As a result, a relatively short and constant settling time can be used for all samples to give reproducible results, provided that the settling time is longer than the longest recovery time. According to the experimental data obtained for a variety of samples by the inventors, 10 ms combined flush pulse duration plus settling time was sufficient in all cases.
The actual device for implementing the linear axial field may be any configuration described in U.S. Pat. No. 5,847,386. However, the tilted rod and tapered rod configurations are not compatible with the establishment of a well defined bandpass through the cell. Segmented rods are applicable to the present invention, but their enactment is awkward and they do not generate a continuous axial field or potential gradient (there are sequential periods of acceleration/deceleration, which adversely affects the temporal response). A further means of providing an axial field is to arrange electrodes external to the multipole such that an external axial field penetrates through the openings between the multipole rods and produces an axial field (though at relatively reduced field strength) inside the multipole. It is believed that most suitable configuration is that using auxiliary electrodes located between the rods of a multipole rod set. These are typically (but not necessarily) shaped so as to generate a nearly linear field along the multipole axis.